Gastro-resistant and ethanol-resistant controlled-release formulations comprising hydromorphone

ABSTRACT

The invention provides a controlled-release composition comprising hydromorphone or a pharmaceutically acceptable form thereof in association with a gastro-resistant and ethanol-resistant compound and method of use thereof.

BACKGROUND OF THE INVENTION

Hydromorphone is a potent opioid used for chronic pain relief. Untilrecently, hydromorphone was available on the market as Palladone™, whichis a controlled-release capsule formulation. In this formulation,hydromorphone is released into a patient's bloodstream gradually, thusallowing the patient to take the hydromorphone capsule only once perday. Gradual release of hydromorphone is important because hydromorphonein high doses has significant and dangerous side effects. Among theseeffects are respiratory depression, hypotension, carbon dioxideretention, and elevation of cerebrospinal fluid pressure, which may leadto death of the patient. Thus, it is important that hydromorphone bereleased into the patient's bloodstream gradually, rather than acutely.

Recently, it has been found that alcohol increases release ofhydromorphone from Palladone™, leading to adverse effects so severe thatFDA has recently asked the manufacturer of Palladone™ to voluntarilyremove Palladone™ from the market. (See Jul. 13, 2005 FDA Alert ForHealthcare Professionals.www.fda.gov/cder/drug/InfoSheets/HCP/hydromorphoneHCP.htm. According tothe FDA release, concentrations of hydromorphone in the blood increasedover fivefold when 12 mg Palladone™ capsules (the lowest available dose)were taken with 8 ounces of 40% (80 proof) alcohol. Even smaller amountsof alcohol consumed by certain patients accelerated release ofhydromorphone. For example, studies showed that taking Palladone™ with amixed drink (equivalent to 20% alcohol) or even with one beer(equivalent to 4% alcohol) result in increased hydromorphoneconcentration, compared to taking Palladone™ without alcohol.(Id.)Accordingly, there is an immediate need for a gastro-resistant andethanol-resistant controlled release hydromorphone formulation.

SUMMARY OF THE INVENTION

The present invention fills the foregoing need by providing such agastro-resistant and ethanol-resistant controlled release hydromorphoneformulation. In one aspect, the invention provides a controlled-releasecomposition comprising hydromorphone or a pharmaceutically acceptableform thereof in association with a gastro-resistant andethanol-resistant compound. The composition may comprise hydromorphonein a matrix of a gastro-resistant and ethanol-resistant compound.Alternatively, the gastro-resistant and ethanol-resistant compound mayform a coating around the matrix containing hydromorphone. Further, thegastro-resistant and ethanol-resistant compound may be present in boththe matrix and the coating of the composition. The composition may beformulated as a capsule, a tablet, a pill, a pellet or a granule.

In another aspect, the invention provides a method of treating a mammal,including humans having chronic pain comprising orally administering tosuch mammal the controlled-release composition described above once aday.

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of this application, the following definitions shallapply:

The term “hydromorphone” shall mean hydromorphone or anypharmaceutically acceptable salt thereof, including without limitationhydromorphone hydrochloride.

The term “gastro-resistant” shall mean the ability to delay or preventthe release of hydromorphone in the acidic gastric medium of a patient'sstomach so that the hydromorphone is released gradually into thepatient's bloodstream without any adverse effects. The term“ethanol-resistant” shall mean the ability to delay or prevent therelease of hydromorphone induced by alcohol consumption.

Generally, the embodiments of the present invention relate to acomposition comprising hydromorphone in association with agastro-resistant and ethanol-resistant compound. The composition may beformulated as a capsule, a tablet, a pill, a pellet, or a granule.

Examples of suitable gastro-resistant and ethanol-resistant substancesinclude, but are not limited to alginic acid, glyceryl monostearate,glyceryl palmitostearate, carnauba wax, microcrystalline wax, white wax,yellow wax, and ethylcellulose with less than 47% of ethonyl groups, asdescribed in Handbook of Pharmaceutical Excipients, Fourth Edition,(edited by Rowe, Sheckey, and Weller, Pharmaceutical Press, 2003). Theformulations according to embodiments of the present invention maycomprise auxiliary excipients such as for example diluents, binders,lubricants, surfactants, disintegrants, plasticisers, anti-tack agents,opacifying agents, pigments, and the like. As will be appreciated by thepeople skilled in the art, the exact choice of excipient and theirrelative amounts will depend to some extent on the final oral dosageform. Suitable diluents include, for example, pharmaceuticallyacceptable inert fillers such as microcrystalline cellulose, lactose,starch, dibasic calcium phosphate, saccharides, and/or mixtures of theforegoing. Examples of microcrystalline celluloses include (Avicel PH200, Avicel PH 102, Avicel PH 112, Avicel PH 101, Avicel PH 3020.Non-limiting examples of lactose include lactose monohydrate. Inaddition, mannitol, sucrose, and dextrose may be used. Suitable bindersinclude, for example, starch, povidone, low viscosityhydroxypropylmethylcellulose such as Methocel E-5 Prem. LV,pregelatinised starch, hydroxypropylcellulose and/or mixtures of theforegoing. Suitable disintegrants include, for example, crosslinkedpolyvinyl pyrrolidone, various starches, such as potato starch, cornstarch, rice starch, and modified starches, crospovidone, sodium starchglycollate croscarmellose sodium, and the like or mixtures thereof.Suitable lubricants, including agents that act on the flowability of thepowder to be compressed are, for example, colloidal slilcon dioxide suchas Aerosil® 200; talc; stearic acid, magnesium stearate, calciumstearate and sodium stearyl fumarate.

As indicated above, the dosage forms of the present invention maycomprise auxiliary, excipients such as for example lubricants,plasticisers, anti-tack agents, opacifying agents,) pigments, and suchlike. As will be appreciated by those skilled in the art, the exactchoice of excipients and their relative amounts will depend to someextent on the final oral dosage form.

A person skilled in the art will recognize that the gastro-resistant,and ethanol-resistant substances can be used in the matrix, as well asthe coating of the composition. Accordingly, in one embodiment, thepresent invention is a composition comprising hydromorphone and agastro-resistant and ethanol-resistant substance, wherein thegastro-resistant and ethanol-resistant substance serves as a matrix ofthe composition.

Non-limiting examples of the gastro-resistant and ethanol-resistantsubstances especially suitable for the matrix of the composition includeglyceryl monostearate and glyceryl palmitostearate.

The composition according to embodiments of the present invention may beprepared by many methods known to a skilled artisan. For example,granules for preparing tablets according to the invention can bemanufactured in accordance with standard procedures in whichhydromorphone may be combined with suitable excipients prior to mixingand forming compressible granules by adding solution of a binder in alow or high shear mixer or by fluidized bed granulation. The granulesare dried, preferably in a fluidized bed dryer. The dried granules aresieved and mixed with lubricants and disintegrants. Alternatively, themanufacture of granules can be achieved by direct mixing of the directlycompressible excipients or by roller compaction.

In some cases, it may be desirable to provide a formulation, wherein apatient receives a small predetermined dose of hydromorphone immediatelyupon ingestion of the formulation, while the bulk of hydromorphone isreleased slowly over time. Thus, it would be desirable in certainembodiments to select a coating which includes the predetermined amountof the hydromorphone and an encapsulating agent which is readilydissolved in either the gastric fluid of a patient or alcohol.Non-limiting examples of such agents are chitosan, poly(butylmethacrylate, (2-dimethyl aminoethyl) methacrylate, methyl methacrylate)1:2:1 (also known as Eudragit E 100, produced by Röhm GmBH), andpoly(ethyl acrylate, methyl methacrylate) 2:1 (also known as Eudragit E12.5, produced by Röhm GmBH).

After ingestion of the formulation, the encapsulating agent woulddissolve quickly, thus releasing said predetermined amount ofhydromorphone. At the same time, the bulk of hydromorphone in complexwith the gastro-resistant and ethanol-resistant compound will not beimmediately available to the patient and will be released slowly upontime. A person skilled in the art will recognize that differentembodiments are possible to achieve this goal. For example, acomposition with more than one coating is possible. In this embodiment,the outermost coating will quickly disintegrate in the gastricenvironment thus releasing hydromorphone, while the bulk ofhydromorphone can be protected by an inner coating comprising thegastro-resistant and ethanol-resistant compound.

In another embodiment, the present invention comprises a compositionincluding hydromorphone and one or more gastro-resistant andethanol-resistant substances, serving as coating agents for theformulation. Non-limiting examples of gastro-resistant andethanol-resistant substances suitable for coating are carnauba wax,microcrystalline wax, white wax, yellow wax, and ethyl cellulose withless than 46.5% of ethonyl groups. It is preferred that amount ofgastro-resistant and ethanol-resistant coating applied is from 5% to 30%by weight with regard to the total weight of the matrix of thecomposition.

The first step of the process for the preparation of the compositionwith controlled release of hydromorphone is anhydrous granulation ofhydromorphone and dried pharmaceutically acceptable auxiliary substancesso that their weight loss at drying is preferably less than 1.0%.Organic solvents to be used in the process of anhydrous granulationshould, preferably, contain less than 0.2% of water. The process ofanhydrous granulation is carried out in such a way that a driedsurfactant is dissolved in an organic solvent at room temperature andthe obtained solution is sprayed in a fluidized bed granulator onto ahomogenous powdery mixture containing hydromorphone, a dried bindersoluble in organic solvents, a dried cellulose ether and other driedpharmaceutically acceptable auxiliary substances. The organic solventsto be used for that purpose are selected from the group of alcohols,ketones, esters, ethers, aliphatic hydrocarbons, halogenatedhydrocarbons, cycloaliphatic, aromatic, heterocyclic solvents andmixtures thereof. The plastic mixture obtained in the process ofanhydrous granulation is formed into granules or pellet cores by commonpharmaceutical technological processes such as extruding andspheronizing methods. The pellet cores or granules so formed are driedin a fluidized bed or in a chamber dryer at the temperature of inlet airfrom 35° C. to 45° C. until the weight loss at drying is less than 1.0%of the total weight of the pellet cores or granules. Under the additionof dried pharmaceutically acceptable auxiliary substances, dry pelletcores or granules may be compressed into tablets, which in furtherprocedure are coated with a gastro-resistant, ethanol resistant coating.In view of the porosity of the tablets, also one or more intermediatecoatings may be applied between the tablet and the gastro-resistant andethanol-resistant coating. Alternatively, pellet cores or granulesprepared by means of anhydrous granulation may be coated withgastro-resistant and ethanol-resistant coating and then filled intocapsules or bags or compressed into tablets under addition of driedpharmaceutically acceptable auxiliary substances. In view of theporosity of pellet cores or granules, also one or more intermediatecoatings may be applied between the pellet core or granule and thegastro-resistant coating.

The dosage forms of the present invention may comprise auxiliary,excipients such as, for example, lubricants, plasticisers, anti-tackagents, opacifying agents, pigments, and such like. As will beappreciated by those skilled in the art, the exact choice of excipientand their relative amounts will depend to some extent on the final oraldosage form.

The gastro-resistant and ethanol-resistant compounds disclosed hereinare ethanol-insoluble. Accordingly, a skilled artisan will appreciatethat the administration of the composition wherein hydromorphone releaseis controlled by these compounds will not result in increased levels ofhydromorphone in the blood of a patient who has or will have consumed anequivalent of as much as 47 ml of alcohol (an equivalent of eight ouncesof a 20% ethanol solution, which is a typical alcohol content for amixed drink) within eight hours of the administration of a compositionaccording to the embodiments of this invention.

According to another aspect of the present invention, the compositionsof this invention may comprise active agents other than hydromorphone.The compositions of this invention are especially advantageous for theactive agents, which are harmful if their release from the formulationis accelerated due to destruction of the coating.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

1. A controlled-release composition comprising hydromorphone or apharmaceutically acceptable form thereof in association with agastro-resistant and ethanol-resistant compound.
 2. Thecontrolled-release composition of claim 1, said controlled-releasecomposition being in the form of a capsule, a tablet, a pill, a pelletor a granule.
 3. The controlled-release composition of claim 2 whereinthe gastro-resistant and ethanol-resistant compound is in a matrix ofthe composition.
 4. The controlled-release composition of claim 3,further comprising at least one encapsulating agent.
 5. Thecontrolled-release composition of claim 2, wherein the gastro-resistantand ethanol-resistant compound comprises a coating of thecontrolled-release composition.
 6. The controlled-release composition ofclaim 5, further comprising at least one encapsulating agent, whereinsaid at least one encapsulating agent forms the outermost layer of thecontrolled release composition.
 7. The controlled-release composition ofclaim 5, further comprising at least one encapsulating agent, whereinsaid at least one encapsulating agent forms a layer located between amatrix and a coating of the controlled-release composition.
 8. Thecontrolled-release composition of claim 2, wherein the gastro-resistantand ethanol-resistant compound is selected from the group consisting ofalginic acid, glyceryl monostearate, glyceryl palmitostearate, carnaubawax, microcrystalline wax, white wax, yellow wax, ethylcellulose withless than 46.5% of ethonyl groups, and any combination thereof.
 9. Amethod of treating a mammal having chronic pain comprising orallyadministering such mammal the composition of claim 2 once a day, whereinadministration of said composition to the mammal who has or will haveconsumed an equivalent of 47 ml of ethanol within 8 hours ofadministration does not result in an elevated level of hydromorphone inblood of said mammal.
 10. The method of claim 9, wherein said mammal isa human.
 11. A controlled-release composition comprising one or moreactive agents in association with a gastro-resistant andethanol-resistant compound, wherein an accelerated release of at leastone of said one or more active agents from said controlled-releasecomposition is potentially harmful to a subject who intakes saidcontrolled-release composition.